Elucidation of the mechanisms by which Ms4a genes regulate neurodegeneration in Alzheimer's Disease and related disorders

Current therapeutic interventions for treating neurodegenerative disorders, including Alzheimer’s Disease (AD), frontotemporal dementia (FTD), multiple sclerosis (MS), and Amyotrophic lateral sclerosis (ALS), are highly limited in both number and efficacy, suggesting novel approaches are needed. Most prior research has focused on developing strategies for treating each of these diseases individually, but these endeavors have largely failed in advancing efficacious therapeutics. We have recently generated exciting data that offers the promise to overcome this gap in neurodegenerative research. We find that genetic deletion of one of the members of the membrane spanning 4a (Ms4a) family of genes, Ms4a6c, significantly improves cognitive, behavioral, and cellular phenotypes in mouse models of AD, FTD, ALS, and MS. Moreover, we and others have demonstrated that polymorphisms in Ms4a genes are strongly linked to altered susceptibility to neurodegenerative disorders, including ALS and AD. The link between Ms4a genes and neurodegeneration has been best studied in AD, where current data suggest that Ms4a polymorphisms are among the strongest genetic modifiers of AD risk. Together, this research suggests that therapeutic strategies targeting Ms4a genes are likely to be beneficial in treating many neurodegenerative disorders. However, to date we have only examined the effect of deleting a single Ms4a gene on neurodegeneration. Although Ms4a6c deletion results in significant improvement in all phenotypes examined across many neurodegenerative disorders, the phenotypic rescue remains incomplete. The Ms4a family consists of 17 genes, and other family members, including Ms4a4a, Ms4a4e, and Ms4a6e have also been strongly genetically linked to altered risk of developing neurodegenerative disorders. However, most of these AD associated polymorphisms localize to non-coding regions of this gene family, and their effect on MS4A function remains largely unknown, making it unclear whether loss of function or gain of function of these genes is protective against neurodegeneration. We have found that similarly to Ms4a6c, the expression of many other Ms4a genes is upregulated in multiple mouse models of neurodegeneration. Together, these observations have led us to hypothesize that deletion of other Ms4a family members might also improve neurodegenerative phenotypes, and we have generated significant pilot data in support of this hypothesis. Our first aim will therefore take advantage of novel mouse genetic reagents we have generated to enable us to probe the effect of deleting (or over-expressing) other Ms4a family members individually or deleting multiple Ms4a family members simultaneously on neurodegenerative phenotypes. In our second aim, we will build on considerable pilot data to elucidate the mechanisms by which Ms4a genes regulate neurodegeneration, a process which to date remains entirely unexplored. Together, these aims will provide significant insight into the role that Ms4a genes play across neurodegenerative diseases and take us one significant step closer to developing therapeutic approaches targeting these genes. Project Number: 1R01AG089801-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Paul Greer | Institution: UNIV OF MASSACHUSETTS MED SCH WORCESTER, WORCESTER, MA | Award Amount: $445,130 | Activity Code: R01 | Study Section: Molecular Neurogenetics Study Section[MNG] View on NIH RePORTER: https://reporter.nih.gov/project-details/11135677